In humans, each hair follicle goes through repeated cyclical periods of growth including an active growth stage (anagen), which can persist for approximately 2 to 6 years; a transition phase (catagen), which lasts for only a week or two; and a resting period (telogen), which lasts 3 to 4 months. The hair is shed at the end of the telogen phase, and a new hair is grown as the cycle repeats. In the human scalp, which contains approximately 100,000 hair follicles, normally about 86% are in anagen, 1% are in catagen and 13% are in telogen. Therefore, in a normal human adult, approximately 100 hairs are shed from the scalp per day.
Excessive hair loss, or alopecia, may be classified as being one of two types, non-scarring alopecia and scarring alopecia, and can be caused by a wide variety of factors. For example, non-scarring alopecia has been attributed to genetics and advanced age; administration of drugs such as anti-cancer chemotherapeutic drugs and contraceptives; topical use of chemical treatments, such as hair dyes, permanent wave solutions, and straighteners; diseases, such as leprosy or syphilis; illness; allergy; and hair follicle infection. Scarring alopecia may be a consequence of burns (accidental or post surgical from cryosurgery or laser surgery) or trauma, which often causes destruction of follicles.
The most common type of human hair loss is androgenetic alopecia (also known as androgenic alopecia), which is a non-scarring hair loss of telogen hairs caused by an excessive androgen effect in genetically susceptible men and women. Androgens trigger the miniaturization or atrophy of terminal follicles that normally produce thick scalp hair and transforms them into vellus-like follicles, eventually yielding fine, downy hair that is barely perceptible. Androgenetic alopecia is expressed in males as baldness of the vertex of the scalp and is commonly referred to as male pattern baldness. In females, androgenetic alopecia appears as diffuse hair loss or thinning of the frontoparietal areas. As alopecia progresses with age, hairs in these predisposed areas miniaturize and appear to change from terminal hairs to resemble vellus hairs. In addition, as androgenetic alopecia continues, the number of hairs in the active growth anagen phase decreases while there is an increase the number of hairs in the telogen phase.
Androgenetic alopecia, which is sometimes referred to as "common baldness" or "male pattern baldness," independent of its causes, is the cutaneous aping of a particular zone (i.e., the scalp). Androgenetic alopecia can be defined, on one hand, as atrophy, sclerosis or minaturization of the hair follicles. On the other hand, androgenetic alopecia can be defined as a progressive shortening of the average duration of the anagen stage, which results in vellus hair prior to complete disappearance.
Hair loss is an extremely common condition among healthy adult males, and also occurs frequently in adult females. In fact, some degree of alopecia on the vertex from puberty onwards is thought to be a universal phenomenon in both men and women (R. P. R. Dawber (1987) Dermatologica 175:23-28). Alopecia is also frequently observed in both pre- and post-pubertal patients as a side effect of anti-cancer chemotherapy, (A. M. Hussein, et al. (1990) Science 249:1564-1566, B. W. Cline, (1984) Cancer Nursing 7:221-228; A. F. Hood (1986) Med. Clin. North Am. 70:187-209).
Despite the widespread occurrence of androgenetic alopecia, the need for prevention and therapy still exists. The lack of a proven and effective treatment for androgenetic alopecia has caused many afflicted individuals to adopt the practice of wearing a wig or toupee. Another extreme measure used to combat androgenetic alopecia, hair transplant surgery, is not available as an option in many cases (i.e., following chemotherapy) and offers, at best, only a partial remedy. At the same, the latter treatment suffers from a number of disadvantages, including the need for surgery.
A common non-surgical treatment for stimulating hair growth is minoxidil (The Upjohn Company, Kalamazoo, Mich.). A solution of minoxidil as active ingredient is known as Rogaine.RTM. As stated in the Rogaine.RTM. Patient Information Booklet (The Upjohn Company, Kalamazoo, Mich., revised June, 1992) minoxidil is a vasodilatory drug which has serious side effects when administered orally for the treatment of hypertension. At the same time, topical application of minoxidil for the treatment of androgenetic alopecia is only partially effective and suffers from a number of disadvantages. For example, minoxidil is only recommended for treatment of male pattern alopecia of the vertex (i.e., frontal recession), has to be applied twice daily for at least four months, and requires a normal scalp with no local abrasions, dermatitis or sunburn--conditions that can increase absorption into the blood stream and the concomitant risk of side effects. Further, minoxidil is of limited effectiveness. For example, there is no significant increase in terminal hair regrowth between minoxidil and placebo treatment groups after four months of treatment (refer to the Rogaine.RTM. Patient Information Booklet, The Upjohn Company, Kalamazoo, Mich., revised June, 1992). In patients who do respond to minoxidil treatment, the new hair is likely to be shed within a few months after stopping treatment.
Androgens are responsible for many physiological functions in both males and females. Androgen action is mediated by specific intracellular hormone receptors expressed in androgen responsive cells. Testosterone, the major circulating androgen, is secreted by Leydig cells of the testes under the stimulation of pituitary-derived luteinizing hormone (LH). However, reduction of the 4, 5 double bond of testosterone to dihydrotestosterone (DHT) is required in some target tissues, such as prostate and skin, for androgen action. Steroid 5.alpha.-reductases in target tissues catalyze conversion of testosterone to DHT.
The requirement for DHT to act as an agonist in these target tissues has been highlighted by studies of steroid 5.alpha.-reductase deficient individuals who have vestigial prostate glands and do not suffer from male pattern baldness (see McGinley. J. et al., The New England J. of Medicine, 300, 1233 (1979)). Thus, inhibition of the conversion of testosterone to DHT in these target tissues is anticipated to be useful in the treatment of a variety of androgen responsive diseases (i.e., benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism).
Additionally, it has been discovered that two isozymes of 5.alpha.-reductase exist in humans which differ in their tissue distribution, affinity for testosterone, pH profile and sensitivity to inhibitors (see Russell, D. W. et al., J. Clin. Invest., 89, 293 (1992); Russell, D. W. et al., Nature, 354, 159 (1991)). The steroid 5.alpha.-reductase deficient individuals studied by Imperato-McGinley are deficient in the type 2,5.alpha.-reductase enzyme (Russell, D. W. et al., J. Clin. Invest., 90, 799 (1992); Russell, D. W. et al., New England J. Med., 327, 1216 (1992)), which is the predominant isozyme present in the prostate, while the type 1 isozyme is predominant in the skin. The relative value of isozyme specific and dual inhibitors of the two isozymes of 5.alpha.-reductase will depend upon the type of disease treated (benign prostatic hyperplasia, prostate cancer, acne, male pattern baldness or hirsutism) as well as the stage of the disease (prevention versus treatment) and the anticipated side-effects in the intended patients (for example treatment of acne vulgaris in pubescent males).
Because of their valuable therapeutic potential, testosterone 5 alpha reductase inhibitors have been the subject of active research worldwide. For example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 224 (1973); Robaire, B. et al., J. Steroid Biochem., 8, 307 (1977); Petrow, V. et al., Steroids, 38, 121 (1981); Liang, T. et al. J. Steroid Biochem., 19, 385 (1983); Holt, D. et al., J. Med. Chem., 33, 937 (1990): U.S. Pat. No. 4,377,584, U.S. Pat. No. 4,760,071 and U.S. Pat. No. 5,017,568. Several particularly promising 5.alpha.-reductase inhibitors are: (1) MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar; (2) SKF-105657 (SmithKline Beecham); and (3) cyproterone acetate.
Finasteride (17.beta.-(N-tert-butylcarbamoyl )-4-aza-5.alpha.-androst-1-ene-3-one), which is marketed by Merck & Co., Inc. under the tradename PROSCAR.RTM., is an inhibitor of 5.alpha.-reductase 2 and is known to be useful for the treatment of hyperandrogenetic conditions. See e.g., U.S. Pat. No. 4,760,071. Finasteride is currently marketed in the United States and worldwide for the treatment of benign prostatic hyperplasia. Finasteride's utility in the treatment of androgenetic alopecia is also disclosed in the following documents: EP 0 285,382, published Oct. 5, 1988; EP 0 285 383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian Patent no. 1,302,276.
Androgens are the most obvious regulators of human hair growth in both sexes. Androgens have pradoxically contrasting effects on follicles depending on their location in the body. Androgens stimulate hair growth in many locations (i.e., beard, axilla) while inhibiting scalp hair growth in genetically predisposed individuals. Androgens act on the hair follicles via the dermal papilla, presumably by altering the production of regulatory factors effecting the dermal papilla cells. Cultured dermal papilla cells secrete soluble, proteinaceous factors which are mitogenic for other dermal papilla cells, outer root sheath cells, epidermal keratinocytes and endothelial cells. Androgen sensitive cells from beard or balding scalp reflect their in vivo androgenetic responses by responding to testosterone, by increasing (i.e., beard) or decreasing (i.e., balding) their mitogenic ability.
The dermal papilla is a connective tissue structure situated at the base of hair follicles. The dermal papilla is composed of specialized fibroblast cells which demonstrate major changes in terms of cell morphology, vascularization, composition and volume of extracellular matrix. During anagen the dermal papilla cells show intracellular structures indicating on going protein synthesis and there is an active vascularization process, whereas during the telogen it is quiescent and non vascularized.
The dermal papilla extracellular matrix contains collagen laminin fibronectin and haparin sulfate proteoglycan. During the transition form anagen to catagen the extracellular matrix diminishes in volume and in the telgoen phase it is almost nonexistent. Also in the telogen phase fibronectin, laminin and proteoglicans diminwhile the collagen content is increased in the interfollicular dermis and in the dermal papilla. There is some evidence indicating proteoglicans involvement in the hair growth process in addition to the above mentioned changed pattern of expression during the hair growth cycle. Injection of glycosamonoglycans in to skin of rabbits stimulated hair growth. The accumulation of proteoglycans in the skin, like in pretibial myxedema is associated with hypertrichosis.
The present invention relates to the use of Relaxin, in the manufacture of medicaments having a novel application, to a method of use in which relaxin is utilized for the treatment and prevention of certain conditions and to pharmaceutical compositions comprising relaxin. Relaxin otherwise known as Cervilaxin, and formerly referred to as Releasin, is a polypeptide hormone secreted by the corpora lutea of many mamalian species during pregnancy.
As described in U.S. Pat. No. 3,096,246, the contents of which are incorporated herein by reference, relaxin is present in the ovaries of animals and may be extracted therefrom. It is believed to be a hormone of pregancy and has aroused great interest in the field of medical research. For example, it has been known to cause uterine cervix relaxation in cows; to increase the dilatability of uterine cervix in ovariectomized estrogen-primed hogs; to cause definite milk let-down in sheep, and, to a lesser extent, in cows, and to cause marked lobulo-alveolar growth of the mammary gland in rats; and, in the clinic, it has been found to cause dilation of the uterine cervix in near-term pregnant women who fail to dilate after injections of pitocin, and to stop premature labor in certain female patients, allow them to go through to term.
EP 08664g, the contents of which are incorporated he rein by reference, relates to the molecular cloning and characterization of the gene sequence coding for porcine relaxin. Thus, recombinant DNA techniques for the preparation of procine relaxin were described more than ten years ago. However, before the advent of the present invention, application of relaxin has been restricted essentially to pregnancy- and gynecologically-related uses.